Diffuse and Focal Brain Injury in a Large Animal Model of PTE: Mechanisms Underlying Epileptogenesis
Abstract
Military traumatic brain injury (TBI) is a heterogeneous injury, often involving both focal and diffuse components, and sometimes an accumulation of mild repetitive injuries such as concussion. The high incidence of post-traumatic epilepsy (PTE) is well-established. However, the degree to which each of these components of TBI leads to alterations in brain activity that ultimately results in PTE is unknown, as is the mechanism of this transition. In order to address these problems, a preclinical model of PTE must accurately reproduce the diffuse as well as the focal components of injury. Since it is known that injury to the connections between neurons, or white matter, is key to diffuse brain injury, we propose that a large animal model (pig) may be the only way to investigate the contributions of each component of traumatic injury to the development of epilepsy. The pig brain has adequate white matter pathways and a shape and mass much closer to that in the human in comparison to rodent models. To understand how and when PTE develops and how to treat or prevent it, we must first understand what happens in the brain between the traumatic insult and the development of seizures. We have recently discovered that the hippocampus, a structure in the brain often associated with epilepsy, is abnormally excitable after diffuse traumatic injury in our pig model of TBI, displaying characteristic activity that is sometimes seen in human patients who develop epilepsy. As this diffuse injury is known to be primarily injury to the white matter (as distinct from loss of neurons, for example), our findings suggest that damage to the pathways into the hippocampus can alter its circuitry, which may predispose it to developing seizures. Therefore, we hypothesize that brain trauma via white matter injury leads to the loss of inputs into the hippocampus, altering its intrinsic circuitry. We hypothesize that over time this loss of input leads to a compensatory mechanism, whereby the hippocampus acquires a stronger response to a given level of input, leading to abnormal patterns of activity that can lead to epilepsy. To test these hypotheses, we have established three major goals. Initially, we wish to determine to what extent each component of traumatic injury, as well as which combinations may result in developing PTE. We will accomplish this by subjecting pigs to combinations of diffuse, focal, and repetitive injuries and measuring the occurrence of PTE. Secondly, we wish to elucidate what abnormal changes in the circuitry within and incorporating the hippocampus after injury lead to epileptic and epileptiform patterns of brain activity and how often, or whether they result in seizures. We will accomplish this by chronically implanting electrodes within the hippocampus and on the surrounding cortex of injured pigs and analyzing the recorded signals, as well as correlating these findings with pathological microscopic changes in the brain postmortem. Thus, we propose to combine our unique expertise modeling human TBI in the pig and our neurosurgical expertise with the expertise of neurologists specializing in epilepsy trained to evaluate chronic recordings of brain activity for epileptic, or epileptiform patterns. Finally, we wish to measure certain substances in the blood thought to be indicators of TBI severity and to determine if they predict the development of PTE. Therefore, with these goals we will develop a preclinical model of PTE that both investigates the mechanisms by which different components of TBI may lead to PTE such as focal vs. diffuse injury, or repetitive injury. After validation, this new model will serve as a platform for future treatment targets and therapy development. The strength of our proposal is the unique combination of large animal TBI, pathology, electrophysiology, and biomarkers that will allow us to address fundamental questions of how PTE develops. Our proposal addresses a number of the Epile
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610675
Entities
People
- John A Wolf
Organizations
- United States Army
- University of Pennsylvania